Paula Kavathas

Associate Professor Laboratory Medicine, Genetics and Immunobiology

B.A. University of Wisconsin, Madison, 1972
Ph.D. University of Wisconsin, Madison, 1980

Research Interests:

Genetic Regulation in T Cell Development
Molecular Genetics of Lymphocyte Surface Proteins

Honors:

Leukemia Society of America Scholar

The interests of our lab are on developmental and functional aspects of the immune system. Lymphoid cells that mediate cellular immunity are called T cells. They mature and differentiate in the thymus exiting into the periphery as either CD4+ or CD8+ T cells. One area of research is on the CD8 proteins, alpha and beta. We are determining how the genes are regulated during development and how the CD8 proteins function on the T cell surface as receptors. The other research area is on characterizing immune responses to the bacteria, Chlamyiai Trachomatis.

Current Research

Gene Regulation: We created transgenic animals with pieces of human DNA from the human CD8 gene complex (alpha and beta genes) and were able to obtain correct developmental expression of the genes. To localize regulatory elements, we performed sequence analysis, DNase I hypersensitivity mapping, and MAR (matrix attachment region) analysis. We identified several striking regions and are performing further transgenic and knockout studies to firmly establish the presence of regulatory elements.

Structure/Funtion Analysis: The CD8 protein interacts with ligands on the outside of the cell (i.e. MHC class I) and with molecules on the inside of the T cell (i.e. tyrosine kinase p56lck, LAT). It also functions as a coreceptor with the T cell receptor forming a complex with MHC class I. Our goal is to understand in molecular terms how the different protein interactions occur and if there are differences between homo (alpha/alpha) vs. heterodimeric (alpha/beta) forms of CD8. Taking advantage of crystallographic information, we perform mutational analysis and create models of how the proteins interact.

Immune Response to Chlamydia Trachomatis (Ct): Ct is the most common cause of bacterial sexually transmitted disease (STD) worldwide and of ocular trachoma in developing countries. We are characterizing T cell responses to the major outer membrane protein (MOMP) of Ct, a good vaccine candidate. Using special reagents called tetramers, we were able to detect MOMP-specific T cells in the peripheral blood of infected individuals at frequencies that are significant (0.01Ð0.20% of CD8+ T cells). We plan to continue to characterize these cells with regard to homing receptors and function and will determine their role in immunity to Ct.

Figure Legend: Model of the interaction between the immunoglobulin like domains of the CD8a/a homodimer and its ligand MHC class I. The CD8 molecule is in the center flanked by an MHC class I molecule on either side. In blue is the b2m subunit which associates with MHC class I. The proposed interaction was based on mutational studies and the molecules have been pulled apart to better display the interaction. Mutations at positions colored red led to complete inhibition of binding whereas mutations at residues in green had no effect.

Representative Publications:

Kieffer, L.J., Yan, L., Hanke, J.H., and Kavathas, P.B. Appropriate Developmental Expression of Human CD8beta in Transgenic Mice. J Immunol. 159:4907-4912,1997.

Devine, L., Sun, J., Barr, M., and Kavathas, P. Orientation of the Ig-like domains of CD8alpha beta relative to MHC class I. J. Immunol. 162:846-851, 1999.

Devine, L., and Kavathas, P.B. Molecular analysis of protein interactions mediating the function of the cell surface protein CD8. Immunol. Res. 19(2-3):201-210, 1999.

Devine, L., Kieffer, L.J., Aitken, V., and Kavathas, P.B. Human CD8alpha, but not mouse CD8beta, can be expressed in the absence of CD8alpha as a beta beta homodimer. J. Immunol. 164:833-838, 2000.

Updated 28 August 2000